ABSTRACT Current approaches to childhood nephrotic syndrome (NS) are based on routine clinical and laboratory findings that are unable to accurately define the underlying biologic mechanisms, predict clinical course, or select optimal therapy. Treatment of childhood NS lacks a rational mechanistic basis and is associated with significant morbidity and is responsible for 12% of the pediatric end stage kidney disease in the USA. A precision medicine approach is warranted to identify mechanistically discrete disease subgroups, refine biomarkers to assist with molecular classification, identify relevant treatment targets, and improve trial design for pediatric NS. The children's nephrotic syndrome cohort in the Nephrotic Syndrome Study Network (Cohort B) is inclusive of 16 enrolling pediatric centers and associated investigators. In this project, Cohort B will expand to 200 children with incident NS, prospectively followed to define the longitudinal disease course, collect biospecimens to enable comprehensive molecular profiling (phenotype, genotype, immune profiling) for treatment target identification. cNEPTUNE will develop and improve clinical trial methods, endpoints, and systems to enable the conduct of precision medicine trials inclusive of children with nephrotic syndrome. In this renewal proposal, we propose to (a) define genotype-phenotype subgroups of children with incident NS; (b) define non-invasive biomarkers, inclusive of immunological profiles, in functionally defined subgroups of NS; (c) identify candidate therapeutic targets based on the mechanistically defined NS; and (d) develop validated endpoints, trial designs, and systems to foster efficient and effective precision medicine clinical trials for patients with NS.